Seasonal influenza A is a scourge of the young and old, killing more than 250,000 worldwide each year, while creating an economic burden for millions (W.H.O. web site who.int/mediacentre/factsheets/2003/fs211/en/. World Health Organization factsheet 211: influenza (2003)). Pandemic influenza, which occurs when a new virus emerges and infects people globally that have little or no immunity, represents a grave threat to human health: for example, the 1918 “Spanish Flu” pandemic caused an estimated 50 million deaths (Webster, 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci USA 96, 1164-6 (1999); de Wit & Fouchier, Emerging influenza. J Clin Virol 41, 1-6 (2008)). Vaccines have historically been the mainstay of infection control. However, due to rapid antigenic drift, the vaccine antigen needs to be updated annually based on global influenza surveillance (W.H.O. web site who.int/csr/disease/influenza/influenzanetwork/en/index.html. (2008); Carrat & Flahault, Influenza vaccine: the challenge of antigenic drift, Vaccine 25, 6852-62 (2007)), and it is not always fully successful. In addition, some recent H5N1 vaccines have shown promising results (Cinatl et al., The threat of avian influenza A (H5N1). Part IV: Development of vaccines. Med Microbiol Immunol 196, 213-25 (2007); Subbarao & Luke H5N1 viruses and vaccines. PLoS Pathog 3, e40 (2007); Leroux-Roels et al., Broad Clade 2 Cross-Reactive Immunity Induced by an Adjuvanted Clade 1 rH5N1 Pandemic Influenza Vaccine, PLoS ONE 3, e1665 (2008); Baras et al., Cross-Protection against Lethal H5N1 Challenge in Ferrets with an Adjuvanted Pandemic Influenza Vaccine. PLoS ONE 3 e1401 (2008)), but none has been reported to elicit a broad neutralizing response in humans. Neuraminidase inhibitors, especially oseltamavir (Tamiflu), remain the primary antiviral treatment, but they have limited efficacy if administered late in the infection, and widespread use is likely to result in the emergence of resistant viral strains (de Jong et al., Oseltamivir resistance during treatment of influenza A (H5N1) infection, N Engl J Med 353, 2667-72 (2005); W.H.O. Clinical management of human infection with avian influenza A (H5N1) virus. web site who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf).
Influenza A is sub-classified by its two major surface proteins: hemagglutinin (HA or H), which mediates cell entry, first by recognizing host proteins bearing sialic acid on their surface, and second by triggering the fusion of viral and host membranes following endocytosis, allowing viral RNA to enter the cytoplasm; and neuraminidase (HA or N), which cleaves sialic acid from host and viral proteins, facilitating cell exit (Wright et al., Orthomyxoviruses, in Fields Virology Vol. 2 (eds. Knipe, D., Howley, P., Griffin, D., Lamb, R. & Martin, M.) 1692-1740 (Lippincott Williams & Wilkins 2006)). There are 16 HA subtypes and 9 NA subtypes which make up all known strains of influenza A viruses by various combinations of HA and NA (Wright et al. (2006)) (See FIG. 8).
The recent spread of highly pathogenic avian influenza (HPA1), H5N1, across Asia, Europe and Africa raises the specter of a new pandemic, should the virus mutate to become readily transmissible from person-to-person. The evolution of H5N1 into a pandemic threat could occur through a single reassortment of its segmented genome or through the slower process of genetic drift (Wright et al. (2006); Fauci, Pandemic influenza threat and preparedness. Emerg Infect Dis 12, 73-7 (2006). Nearly 400 human H5N1 infections have bees reported since 1997 from 14 countries, with a case mortality rate in the immunocompetent population above 60% (W.H.O. web site who.int/csr/disease/influenza/influenzanetwork/en/index.html. (2008)).
New therapeutic strategies that provide potent and broadly cross-protective host immunity are therefore a global public health priority. Human monoclonal antibody (mAb)-based “passive” immunotherapy is now being used to treat a number of human diseases, including Respiratory Syncytial Virus infection, and it has been proposed how immunotherapy could be used strategically in a viral outbreak setting (Marasco & Sui, The growth and potential of human antiviral monoclonal antibody therapeutics. Nat Biotechnol 25, 1421-34 (2007)).